Pulmonary hypertension (PH) is a complex health problem characterized by elevated blood pressure in the lungs. In an individual with PH, the blood pressure in the pulmonary arteries rises far above the normal level of approximately 14 mm Hg at rest. Typical levels found in a PH patient range from 25 mm Hg at rest up to 30 mm Hg or greater during exertion. This elevated pressure is associated with changes in the small blood vessels in the lungs, resulting in an increased resistance to blood flow through those vessels. This increased resistance, in turn, places a strain on the right ventricle of the heart, which then has to work harder than usual to move an adequate amount of blood through the lungs.
Over time, scarring or fibrosis of the blood vessels in the lungs makes such vessels more resistant to blood flow and some may become completely blocked. Additionally, the presence of scarring within the vessels and inflammation in the lungs increases their overall weight. The continual increase in scar tissue and the extra resistance in the blood vessels results in the heart having to pump much harder in order to move blood through the compromised vessels. Eventually, the heart will enlarge in order to meet that demand and the increase in size is associated with reduced contractility and efficiency which can ultimately lead to heart failure. Unfortunately, it is not until this point that most individuals suffering from PH are diagnosed and treatment started.
There is no cure for PH. Several treatment options exist and include therapeutics to increase blood flow such as anticoagulants to prevent blood clots from forming and calcium channel blockers to relieve constriction in the pulmonary arteries. Additionally, constricted vessels may be relieved by the continuous intravenous or subcutaneous infusion of prostacyclin or prostacyclin analogues through an indwelling catheter. Other therapies include the administration of endothelin antagonists to reduce pulmonary arterial pressure, diuretics to reduce systemic fluid accumulation, digoxin to increase the efficiency of cardiac output, and supplemental oxygen to increase the supply of oxygen to the blood. A PH patient may be on one or a combination of treatments at any given time.
Unfortunately, many patients respond poorly to these therapies or stop responding to them over time. The only remaining option at that point in time is a lung transplant. According to the United Network for Organ Sharing (UNOS) the patient survival rates for all patients that had a lung transplant are 85% at one month, 69% at one year, and 51% at three years for patients transplanted between 1987 and 1992. Results since those years are slightly better. An additional obstacle for patients with PH can be the need for both a heart and lung transplant due to heart failure. An effective therapeutic is needed to help patients of all ages and of either gender as an alternative to this risky and very expensive last resort.
The present invention is particularly useful because the estradiol metabolites used therein have few side effects. In addition, estradiol metabolites can be administered in pharmaceutical formulations that provides for sustained release, an improvement that will provide for the widespread use of the compositions as therapeutics for the treatment of pulmonary hypertension and associated conditions.
Citation of the documents herein is not intended as an admission that any is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on subjective characterization of information available to the applicant, and does not constitute any admission as to the accuracy of the dates or contents of these documents.